Epigenetics in cancer therapy and nanomedicine

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Abstract

The emergence of nanotechnology applied to medicine has revolutionized the treatment of human cancer. As in the case of classic drugs for the treatment of cancer, epigenetic drugs have evolved in terms of their specificity and efficiency, especially because of the possibility of using more effective transport and delivery systems. The use of nanoparticles (NPs) in oncology management offers promising advantages in terms of the efficacy of cancer treatments, but it is still unclear how these NPs may be affecting the epigenome such that safe routine use is ensured. In this work, we summarize the importance of the epigenetic alterations identified in human cancer, which have led to the appearance of biomarkers or epigenetic drugs in precision medicine, and we describe the transport and release systems of the epigenetic drugs that have been developed to date.

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Most cited references 97

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A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.

Y Matsumura, H. Maeda (1986)

We previously found that a polymer conjugated to the anticancer protein neocarzinostatin, named smancs, accumulated more in tumor tissues than did neocarzinostatin. To determine the general mechanism of this tumoritropic accumulation of smancs and other proteins, we used radioactive (51Cr-labeled) proteins of various molecular sizes (Mr 12,000 to 160,000) and other properties. In addition, we used dye-complexed serum albumin to visualize the accumulation in tumors of tumor-bearing mice. Many proteins progressively accumulated in the tumor tissues of these mice, and a ratio of the protein concentration in the tumor to that in the blood of 5 was obtained within 19 to 72 h. A large protein like immunoglobulin G required a longer time to reach this value of 5. The protein concentration ratio in the tumor to that in the blood of neither 1 nor 5 was achieved with neocarzinostatin, a representative of a small protein (Mr 12,000) in all time. We speculate that the tumoritropic accumulation of these proteins resulted because of the hypervasculature, an enhanced permeability to even macromolecules, and little recovery through either blood vessels or lymphatic vessels. This accumulation of macromolecules in the tumor was also found after i.v. injection of an albumin-dye complex (Mr 69,000), as well as after injection into normal and tumor tissues. The complex was retained only by tumor tissue for prolonged periods. There was little lymphatic recovery of macromolecules from tumor tissue. The present finding is of potential value in macromolecular tumor therapeutics and diagnosis.

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Targeting EZH2 in cancer.

Kimberly H Kim, Charles Roberts (2016)

Recent genomic studies have resulted in an emerging understanding of the role of chromatin regulators in the development of cancer. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex, is recurrently mutated in several forms of cancer and is highly expressed in numerous others. Notably, both gain-of-function and loss-of-function mutations occur in cancers but are associated with distinct cancer types. Here we review the spectrum of EZH2-associated mutations, discuss the mechanisms underlying EZH2 function, and synthesize a unifying perspective that the promotion of cancer arises from disruption of the role of EZH2 as a master regulator of transcription. We further discuss EZH2 inhibitors that are now showing early signs of promise in clinical trials and also additional strategies to combat roles of EZH2 in cancer.

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Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer.

Mario Fraga, Esteban Ballestar, Ana Villar-Garea … (2005)

CpG island hypermethylation and global genomic hypomethylation are common epigenetic features of cancer cells. Less attention has been focused on histone modifications in cancer cells. We characterized post-translational modifications to histone H4 in a comprehensive panel of normal tissues, cancer cell lines and primary tumors. Using immunodetection, high-performance capillary electrophoresis and mass spectrometry, we found that cancer cells had a loss of monoacetylated and trimethylated forms of histone H4. These changes appeared early and accumulated during the tumorigenic process, as we showed in a mouse model of multistage skin carcinogenesis. The losses occurred predominantly at the acetylated Lys16 and trimethylated Lys20 residues of histone H4 and were associated with the hypomethylation of DNA repetitive sequences, a well-known characteristic of cancer cells. Our data suggest that the global loss of monoacetylation and trimethylation of histone H4 is a common hallmark of human tumor cells.

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Author and article information

Contributors

Mario F. Fraga: +34 985733644 , mffraga@cinn.es

Agustin F. Fernandez:

ORCID: http://orcid.org/0000-0002-3792-4085

+34 985652411 , agusff@gmail.com

Journal

Journal ID (nlm-ta): Clin Epigenetics

Journal ID (iso-abbrev): Clin Epigenetics

Title: Clinical Epigenetics

Publisher: BioMed Central (London )

ISSN (Print): 1868-7075

ISSN (Electronic): 1868-7083

Publication date (Electronic): 16 May 2019

Publication date PMC-release: 16 May 2019

Publication date Collection: 2019

Volume: 11

Electronic Location Identifier: 81

Affiliations

[1 ]ISNI 0000 0001 2164 6351, GRID grid.10863.3c, Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-FINBA-Hospital Universitario Central de Asturias HUCA, , Universidad de Oviedo, ; Avenida de Roma, 33011 Oviedo, Asturias Spain

[2 ]ISNI 0000 0001 2164 6351, GRID grid.10863.3c, Nanomaterials and Nanotechnology Research Center (CINN-CSIC)-Universidad de Oviedo-Principado de Asturias, ; Avenida de Roma, 33011 Oviedo, Asturias Spain

Author information

Agustin F. Fernandez http://orcid.org/0000-0002-3792-4085

Article

Publisher ID: 675

DOI: 10.1186/s13148-019-0675-4

PMC ID: 6524244

PubMed ID: 31097014

SO-VID: a1ab5a25-bc5f-4c40-a8b4-8a8be2c9110f

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 27 February 2019

Date accepted : 29 April 2019

Funding

Funded by: Plan Nacional de I+D+I FEDER

Award ID: PI15/00892 and PI18/01527

Funded by: Gobierno del Principado de Asturias (ES)

Award ID: IDI/2018/146

Award Recipient : Mario F. Fraga

Funded by: Albert Einstein Cancer Center (US)

Award ID: PROYE18061FERN

Award Recipient : Mario F. Fraga

Funded by: FGCSIC

Award ID: 0348_CIE_6_E

Award Recipient : Mario F. Fraga

Funded by: Miguel Servet II fellowship

Award ID: CPII16/00007

Funded by: Obra Social Cajastur-Liberbank, Spain

Award ID: 0

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ScienceOpen disciplines: Genetics

Keywords: epigenetics,dnmt inhibitors,hdca inhibitors,nanomedicine,nanoparticles,nanocarriers

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ScienceOpen disciplines: Genetics

Keywords: epigenetics, dnmt inhibitors, hdca inhibitors, nanomedicine, nanoparticles, nanocarriers

Epigenetics in cancer therapy and nanomedicine

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Most cited references 97

A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.

Targeting EZH2 in cancer.

Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer.

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